Bone metastasis is a frequent, debilitating and essentially incurable consequence of many types of cancers. Approximately 70% of patients living with advanced breast cancer have metastases to their bones. They suffer from severe bone pain, pathological fractures, life-threatening hypercalcemia, limited mobility and eventually mortality. During cancer bone metastasis, cancer cells and osteoclasts form a vicious cycle so that cancer cells promote osteoclast differentiation and osteoclasts in turn facilitate cancer cell seeding and proliferation in bone. Although current FDA-approved osteoclast inhibitor drugs can attenuate bone metastasis, they are only at best palliative and do not improve overall patient survival. As such, bone metastases remain incurable and better therapeutics is urgently needed. We have recently discovered a new gene that is upregulated in breast cancer and bone metastasis to simultaneously stimulate tumor growth and osteoclast differentiation. Therefore, we hypothesize that it synergistically promotes cancer bone metastasis by orchestrating the vicious cycle between tumor cells and the osteoclastic bone metastatic niche; and its blockade may inhibit both cancer cells and osteoclasts, thereby impeding both arms of the vicious cycle and putting a more effective brake on cancer bone metastasis. Specifically, we propose three aims: Aim 1: Determine how this gene acts in breast cancer cells to promote bone metastasis; Aim 2: Determine how this gene enhances osteoclastogenesis and bone resorption in the bone met niche; Aim 3: Identify and characterize the key molecular targets for this gene. We will establish innovative experimental tools combining in vitro and in vivo, gain- and loss-of-function, genetic and pharmacological approaches. Importantly, our preclinical studies will reveal the translational potential of this novel regulator: 1) its inhibitors may represent exciting new therapeutics to confer dual suppression of primary cancer and bone metastasis; 2) it may serve as an innovative biomarker to predict the propensity of bone metastasis in cancer patients. Understanding of biological principles and eradication of cancer mortality require new knowledge beyond the existing paradigms. Current cancer research often focuses on primary tumors alone. However, most cancer morbidity and mortality relates to metastasis, a complex process involving not only cancer cells but also their microenvironment in the host tissues such as bone. To this end, the proposed investigation creates a new paradigm in cancer research by shifting the focus to novel dual therapeutic targets for cancer cell and osteoclast. Our study will elucidate fundamental mechanisms of cancer and bone biology, provide important insights for bone metastasis prevention and treatment, and identify new signaling pathways as innovative drug targets. Therefore, this study will open exciting new paths to the understanding of cancer etiology and the improvement of cancer outcome, ultimately impact the broader scientific, clinical, and patient community.